Inflammatory reactions result from tissue (cell) injury or infection by foreign pathogens and show a series of complex physiological responses such as enzyme activation, inflammation mediator release, body fluid infiltration, cell movement and tissue destruction, and external symptoms such as erythema, edema, pyrexia, pain and etc., in which various inflammation-mediating factors and immune cells in local blood vessels and body fluids are involved. Also, in some cases, these inflammation reactions result in acute inflammation, granuloma, and chronic inflammations such as rheumatoid arthritis (Goodwin J. S. et al., J. Clin. Immunol., 9: 295-314, 1989).
Rheumatoid arthritis (RA) is an autoimmune disease causing chronic inflammation in the whole body including articulations, and occurs more frequently in women than in men. Its cause has not been clearly known yet, but is assumed to be caused by genetic factors and environmental factors. Accordingly, many researches for finding out the cause of rheumatoid arthritis have been performed. Meanwhile, it has been recently reported that genetic factors play an important role in susceptibility and prognosis prediction of rheumatoid arthritis, and imbalance of epigenetic control on an overall immune response causes an autoimmune disease including rheumatoid arthritis (Richardson B. et al., Clin Immunol, 109, 72-79, 2003).
In rheumatoid arthritis, inflammation mainly occurs in synovial membrane of articulations within a body, and especially, is continued for 6 weeks or more. At the onset of rheumatoid arthritis, a lump (‘Pannus’) including various inflammatory cells is formed from blood of a synovial tissue, which destroys cartilage, erodes the bone around the articulation and causes deformities of in articulations. As a result of joint inflammation, articulation becomes swollen and painful, a movement range of an articulation is limited, and joint becomes red and warm to the touch.
This disease is caused by a disorder in a body immune system. Normally, an immune system within a body performs a role of defending the body against foreign substances such as bacteria. However, the disease is caused by a malfunction of the immune system that attacks the body itself due to unknown factors. Such a state refers to ‘autoimmunity’, in which based on the above described principle, symmetrical inflammation occurs in various joint, especially hand joint, resulting in gradual destruction of articulations for several years to several tens of years. Sometimes, the inflammation may invade other organs (such as lung, heart, eyes, blood vessel, nerves) as well as articulations. Also, the disease causes a disorder in a body function mainly in the prime of lifetime (around one's thirties), and thereby reduces the quality of life and the work efficiency, resulting in a great economic loss.
To date, although many researches on the cause of rheumatoid arthritis have been conducted, the exact cause of rheumatoid arthritis has not been known yet. However, various clinical therapeutic methods on rheumatoid arthritis have been developed, which are divided into a general conservative treatment, a drug therapy, an operation treatment, etc. Because the disease causes joint pain due to chronic inflammation, and deformation and dysfunction in the joint, the goal of treatment of rheumatoid arthritis is to inhibit pain and inflammation, and to minimize the dysfunction of articulations so that a patient can return to a normal life. At present, the most frequently used therapeutic method is a drug therapy. For the drug therapy, according to symptoms, aspirin & non-steroidal anti-inflammatory drugs, a low dose oral steroid, disease modifying anti-rheumatic drugs (DMARDs) (such as an antimalarial drug, sulfasalazine, gold compounds, penicillamine, immunosuppressive drugs (methotrexate (MTX), Immuran), etc.), intra-articular steroid injections and biologicals (such as tumor necrosis factor blocker (etanercept, infliximab, adalimumab), an interleukin-1 receptor antagonist (anakinra), and an anti-CD20 antibody (rituximab)) are used. However, such a drug therapy has a disadvantage in that it may cause side effects such as gastrointestinal disorders, hepatopathy, renal failure, and infection. Accordingly, it is urgently required to develop advanced therapeutic agents with reduced side effects, which can improve manifestations of rheumatoid arthritis, such as inflammation, edema, abnormal neovascularization, bone and cartilage destruction.
Collagen-induced arthritis (CIA) has been used as an animal model of T lymphocytic rheumatoid arthritis (Autoimmunity to Type II collagen: Experimental model of arthritis, J. Exp. Med. 146; 857-868 (1977)). When an experimental mouse susceptible to arthritis is injected with collagen II, arthritis is caused together with formation of pannus and erosion of bones and cartilage within 2 weeks. Like rheumatoid arthritis, collagen-induced arthritis (CIA) also causes a humoral/cellular immune response to collagen.
Meanwhile, a extracellular matrix protein is a constituent playing an important role in tissue frame configuration, and has been reported to perform an important role in maintaining and controlling the shape and function of a tissue through many researches. TGF-β-inducible gene-h3 (βig-h3), a matrix protein induced by transforming growth factor-β (TGF-β), is a protein with a recently known molecular structure, and performs an important role in the control of cellular functions such as adhesion, migration, differentiation and proliferation.
βig-h3 known as a gene related to TGF-β was originally identified by Skonier, et al. It was identified in an A549 cell line (human lung adenocarcinoma cell line) treated with TGF-β1 during in cDNA selection, and was reported to be increased to 20 times or more for 2 days from treatment with TGF-β1 (Stonier, J. et al., DNA cell Biol. 11, 511, 1992). Through DNA sequence analysis of βig-h3, it was found that a βig-h3 protein includes 683 amino acids with an amino-terminal secretory sequence, and a carboxy-terminal Arg-Gly-Asp (RGD) sequence ligand-recognizable by integrins.